Recent accomplishments of our immunotherapy clinical trials include the following: [] Avelumab for metastatic or locally advanced previously treated solid tumors. Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumors while assessing biological correlatives for future development. 53 patients were enrolled (four patients at 1 mg/kg, 13 at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Antidrug antibodies were detected in 2 (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. 31 (58%) of 53 patients in the overall safety population died; no deaths were related to treatment on study. As a consequence of these studies, Phase 2 and 3 studies showed evidence of clinical benefit in a range of human cancers. Avelumab has now been approved by the FDA for the therapy of Merkel cell carcinoma and bladder carcinoma. Phase 3 studies are ongoing in other cancer indications. [] Preliminary results from a Phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-b, in advanced solid tumors. M7824 (MSB0011359C) is a novel bifunctional fusion protein comprised of a fully human IgG1 monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the soluble extracellular domain of transforming growth factor-beta (TGF-b) receptor II, which acts as a TGF-b trap. Preliminary data from a Phase 1 trial of M7824 in patients with advanced solid tumors has now been reported. NCT02517398 is a Phase 1, open-label, 3+3 dose-escalation study. Eligible patients receive M7824 at 1, 3, 10, or 20 mg/kg Q2W until confirmed progressive disease, unacceptable toxicity, or trial withdrawal; treatment beyond progression is generally allowable. The primary objective is to determine the safety and maximum tolerated dose of M7824; secondary objectives include pharmacokinetics (PK), immunogenicity, and best overall response per RECIST v1.1. 16 heavily pretreated patients with ECOG performance status 0-1 have received M7824. Our PK data show a dose-linear increase in exposure starting at a dose of 3 mg/kg; furthermore, M7824 saturates peripheral PD-L1 and sequesters any released plasma TGF-b1, -b2, and -b3 throughout the dosing period in a dose-dependent manner. Grade 3 drug-related treatment-emergent adverse events (TEAEs) occurred in 3 patients; there were no grade 4-5 drug-related TEAEs. BP and colitis responded well to steroids. Colitis and its secondary events of anemia and rectal hemorrhage (in a previously radiated area) were considered dose limiting in one patient. There was preliminary evidence of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical), 1 durable partial response (pancreatic), a 25% reduction in the sum of diameters of target lesions after 2 doses of M7824 (cervical), and 2 cases of prolonged stable disease (pancreatic; carcinoid). Preliminary data from this Phase 1 dose-escalation study suggest that M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of clinical efficacy warrant further study. [] PROSTVAC vaccine. Samarium-153-EDTMP (Quadramet), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This Phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline 30% compared with 4 patients (of 21) in the combination arm, including 3 with PSA decline 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM. [] Peripheral immunoscore. Tumor immunoscore analyses, especially for primary colorectal cancer and melanoma lesions, have provided valuable prognostic information. Metastatic lesions of many carcinoma types, however, are often not easily accessible. We hypothesized that immune cells in peripheral blood may differ among individual patients with metastatic disease, which, in turn, may influence their response to immunotherapy. We thus analyzed immune cell subsets within peripheral blood mononuclear cells to determine if a peripheral immunoscore would have any prognostic significance for patients prior to receiving immunotherapy. Patients with metastatic breast cancer were randomized to receive docetaxel +/- PANVAC vaccine. In another trial, prostate cancer patients with metastatic bone lesions were randomized to receive a bone-seeking radionuclide +/- PROSTVAC vaccine. Predefined analyses of classic immune cell types (CD4, CD8, NK, Tregs, MDSCs, and ratios) revealed no differences in progression-free survival (PFS) for either arm in both trials. Predefined analyses of refined immune cell subsets for which a biologic function had been previously reported also revealed no significant prognostic value in PFS in patients receiving either docetaxel or radionuclide alone; however, in patients receiving these agents in combination with vaccine, the peripheral immunoscore of refined subsets revealed statistically significant differences in PFS (P 0.001) for breast cancer patients receiving docetaxel plus vaccine, and in prostate cancer patients receiving radionuclide plus vaccine (P = 0.004). Larger randomized studies will be required to validate these findings. These studies, however, provide the rationale for the evaluation of refined immune cell subsets to help determine which patients may benefit most from immunotherapy. [] Brachyury. The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation trial enrolled 34 patients at 4 dose levels. Expansion cohorts were enrolled for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. 2 chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising carcinoembryonic antigen (CEA), remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling. A Phase I clinical study involving MVA-brachyury vaccine has also recently been completed.